This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fatty acid synthase (FAS) catalyzes the de novo synthesis of fatty acids and plays an essential role in embryogenesis and energy homeostasis. Inhibitors of FAS have the potential as treamtents for obesity, thereby reducing the risk for related cardiovascular diseases, and for cancer. The animal cytosolic FAS is a 272 kDa multienzyme polypeptide that requires dimerization for activity. Biochemical evidence suggests that FAS subunits assume a coiled, head-to-head architecture. This model has been substantiated by our subsequent structural characterization of single FAS particles by electron microscopy (EM) and is consistent with a recently published crystal structure. However in both structures the carboxyl-terminal domains were not identified, consistent with their known conformational mobility. We propose to continue our investigations of FAS by EM to unequivocally determine locations of these mobile carboxyl terminal domains and to investigate the conformations assumed by the FAS dimer at each step in fatty acid synthesis.